Visible Light Photocatalyzed Cycloaddition Reactions with Cyclopropyl Sulfides

University Of Wisconsin-Madison, Madison WI

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Abstract

DESCRIPTION (provided by applicant): The research and development of new drug therapies is reliant upon synthetic methods that are able to deliver diverse drug-like molecules in a straightforward manner. One common motif found in numerous pharmaceuticals and biologically active natural products are 5- and 7-membered carbocyclic frameworks. As a result, new synthetic methods that allow direct access to these types of scaffolds is necessary for facilitatin the development of these types compounds as therapeutic agents. Cycloaddition reactions are one of the most effective routes for carbocycle synthesis, with [4+2] cycloadditions in particular being a key route for diverse cyclohexane synthesis. However, [3+2] and [4+3] cycloaddition methods for pentacyclic and heptacyclic ring construction remain limited due to the difficulty associated with forming reactive 3-carbon intermediates. Recently, visible light photocatalysis has emerged as a way of mediating cycloaddition reactions through the formation of reactive radical cation intermediates. Unlike other methods for radical cation generation, visible light photocatalysis proceeds under mild conditions and with high efficiency. This proposal aims to utilize visible light photocatalysis as a new approach to [3+2] and [4+3] cycloaddition reactions through the photocatalyzed ring opening of cyclopropyl sulfides to 3-carbon radical cation intermediates. In these transformations the sulfide serves as a redox auxiliary by facilitating the formation and participation of the requisite 3-carbon radical cation intermediate in cycloaddition reactions between alkenes and dienes. In a subsequent step, the sulfide handle can be easily removed under reductive conditions to liberate the desired 5- or 7-membered carbocyclic product. Due to the unique reactivity of radical cation intermediates, these transformations will allow entry into pentacyclic and heptacyclic scaffolds with diverse substitution patterns that would otherwise be challenging to access. In contrast to traditional photochemical methods that require strong UV light and special photoreactors, the proposed transformations will be practical to carry out, requiring standard glassware and a household light bulb to induce photoactivation. In the end, the methods developed in this proposal will provide medicinal and organic chemists a novel strategy-level disconnection for synthesizing biologically active targets that posses pentacyclic and heptacyclic scaffolds. In addition, the findings from this research will lend insight into the development of other useful ring opening transformations that proceed through visible light photoredox catalysis.